Various attempts have been made over the past twenty years to provide semi-permeable microcapsules which were both biocompatible with the body tissue and impermeable to the components of the immune system. Typical of such attempts is that described in U.S. Pat. Nos. 4,352,883 and 4,391,909 to Franklin Lim.
As set forth therein, living tissue or individual cells are suspended in an aqueous solution of a reversibly-gellable material, typically sodium alginate, and droplets of this suspension are allowed to drop into a hardening solution, typically calcium chloride. The temporary capsules so formed are then treated with polylysine and polyethyleneimine to form an outer semi-permeable coating. The core material is reliquified by ion-exchange of the calcium ions.
Survival times of microcapsules produced by this prior art procedure in the animal body were consistently less than 3 weeks, thereby severely limiting the utility of this prior art encapsulation procedure in the treatment of diseases requiring organ transplantation, such as diabetes and liver disease.
In copending U.S. patent application Ser. No. 501,445 filed June 6, 1983 (now U.S. Pat. No. 4,689,293 issued from a continuation of said serial number), assigned to the assignees hereof, the disclosure of which is incorporated herein by reference, there is described an improvement on the above-mentioned prior art procedure which forms a semi-permeable membrane which is both biocompatible and yet is able to protect transplated tissue and cells from destruction by the immune system, such that, in animal tests, a single intraperitoneal transplant of encapsulated islets reversed the diabetic state for more than one year.
The success of the procedure according to the aforesaid application results from a semi-permeable and durable membrane which has an outer surface of biocompatible negatively-charged material. The improved durability, i.e. resistance to rupture, of these microcapsules is due to their near perfect spherical shape and enhanced capsule membrane thickness.
Although the microcapsules produced in the aforesaid pending application represent a significant advance in the treatment of diseases requiring organ transplantation, there is one drawback which inhibits more ideal utilization of the microcapsules and this drawback arises from the relatively large size of the individual microcapsules, which have a diameter from 700 to 1000 .mu.m. Microcapsules produced according to the procedure of the Lim patents also had relatively large diameters of about 1000 to 2000 .mu.m. Microcapsules having these diameters cannot be injected directly into the cardiovascular system, since they would occlude the blood vessel. Accordingly, the microcapsules must be implanted into large body cavities, such as the intraperitoneal cavity.
Location of the implants in an area of the body other than the cardiovascular system results in an increase in the response time of the microcapsules to changing blood conditions, since the microcapsules are not directly in contact with the blood stream. In addition, the relatively large size of the microcapsules compared to the microencapsulated tissue or cells (e.g. about 200 .mu.m for islets of Langerhans) results in a high diffusional resistance for molecules passing through the microcapsule core.
An air jet-syringe pump extrusion method was used in the procedure of the aforementioned pending application and in the Lim patents to product gel droplets containing entrapped islets, or other tissue or cells, from the suspension of the islets in aqueous sodium alginate solution. In this procedure, the sodium alginate solution is extruded through a needle located inside a sheathed tube through which air flows at a controlled rate. As liquid droplets are forced out of the end of the needle by the syringe pump, the droplets are pulled off by the shear forces set up by the rapidly-flowing air stream. The higher the volumetric air flow rate, the stronger are the shear forces, the more quickly the droplets are pulled off the end of the needle and the smaller are the resultant droplets.
However, there are inherent restraints in this prior art procedure which prevent the size of microcapsule produced thereby being less than 700 microns. These restraints are that the viscosity of the gel-forming liquid must be greater than 30 cps in order to form perfectly spherical capsules, the minimum internal diameter of the needle must be greater than 300 .mu.m (24 gauge) so as to prevent blockage of the needle by the islets, and the volumetric air flow rate must remain below 2000 cc/min in order to produce capsules of uniform diameter.